Synthesis and reactions of 11H-benzo[b]pyrano[3,2-f]indolizines and pyrrolo[3,2,1-ij]pyrano[3,2-c]quinolines [1]

Article abstract of DOI:10.1002/jhet.5570400215

2-Methyl-3H-indoles 1 cyclize with two equivalents of ethyl malonate 2 to form 4-hydroxy-11H-benzo[b]pyrano[3,2-f]indolizin-2,5-diones 3, whereas 2-methyl-2,3-dihydro-1H-indoles 9 give under similar conditions regioisomer 8-hydroxy-5-methyl-4,5-dihydro-pyrrolo[3,2,1-ij]pyrano[3,2-c] quinolin-7,10-diones 10. The pyrone rings of 3 and 9 can be cleaved either by alkaline hydrolysis to give 7-acetyl-8-hydroxy-10H-pyrido[1,2-a]indol-6-ones 4 or 5-acetyl-6-hydroxy-2-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-ones 11, respectively. Chlorination of 3 and 9 with sulfurylchloride gives under subsequent ring opening 7-dichloroacetyl-8-hydroxy-10H-pyrido[1,2-a]indol-6-ones 5 or 5-dichloracetyl-6-hydroxy-2-methyl-1,2-dihydro-4H-pyrrolo [3,2,1-ij]quinolin-4-ones 12. The dichloroacetyl group of 5 can be reduced with zinc to 7-acetyl-8-hydroxy-10H-pyrido[1,2-a]indol-6-ones 7. Treatment of the acetyl compounds 4, 7 and 11 with 90% sulfuric acid cleaves the acetyl group and yields 8-hydroxy-10H-pyrido[1,2-a]indol-6-ones 6 and 8, and 6-hydroxy-2-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-ones 13. Reaction of dichloroacetyl compounds 12 with sodium azide yields 6-hydroxy-2-methyl-5-(1H-tetrazol-5-ylcarbonyl)- 1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-ones 14 via intermediate geminal diazides.

Full text of DOI:10.1002/jhet.5570400215

Mar-Apr 2003
297
Synthesis and Reactions of 11H-Benzo[b]pyrano[3,2-f]indolizines and
Pyrrolo[3,2,1-ij]pyrano[3,2-c]quinolines [1]
Thomas Kappe, Peter Roschger, Birgit Schuiki and Wolfgang Stadlbauer*
Department of Chemistry, Organic Synthesis Group, Karl-Franzens University of Graz
Heinrichstrasse 28, A-8010 Graz, Austria/Europe
Received December 20, 2002
2-Methyl-3H-indoles 1 cyclize with two equivalents of ethyl malonate 2 to form 4-hydroxy-11H-
benzo[b]pyrano[3,2-f]indolizin-2,5-diones 3, whereas 2-methyl-2,3-dihydro-1H-indoles 9 give under simi-
lar conditions regioisomer 8-hydroxy-5-methyl-4,5-dihydro-pyrrolo[3,2,1-ij]pyrano[3,2-c]quinolin-7,10-
diones 10. The pyrone rings of 3 and 9 can be cleaved either by alkaline hydrolysis to give 7-acetyl-8-
hydroxy-10H-pyrido[1,2-a]indol-6-ones 4 or 5-acetyl-6-hydroxy-2-methyl-1,2-dihydro-4H-pyrrolo-
[3,2,1-ij]quinolin-4-ones 11, respectively. Chlorination of 3 and 9 with sulfurylchloride gives under subse-
quent ring opening 7-dichloroacetyl-8-hydroxy-10H-pyrido[1,2-a]indol-6-ones 5 or 5-dichloracetyl-6-
hydroxy-2-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-ones 12. The dichloroacetyl group of 5 can
be reduced with zinc to 7-acetyl-8-hydroxy-10H-pyrido[1,2-a]indol-6-ones 7. Treatment of the acetyl com-
pounds 4, 7 and 11 with 90% sulfuric acid cleaves the acetyl group and yields 8-hydroxy-10H-pyrido[1,2-a]-
indol-6-ones 6 and 8, and 6-hydroxy-2-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-ones 13.
Reaction of dichloroacetyl compounds 12 with sodium azide yields 6-hydroxy-2-methyl-5-(1H-tetrazol-5-
ylcarbonyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-ones 14 via intermediate geminal diazides.
J. Heterocyclic Chem., 40, 297 (2003).
Pyrido[1,2-a]indolones C are of interest because they
matic ring giving structure D is rather unlikely and could
not be observed. If 1,2-dihydro-3H-indoles E are used as
1,3-dinucleophilic partner, it could be shown in this work
that E behaves like a N-substituted aniline [3] and only the
regioisomer hydroxy-2-pyridones F are formed.
Cyclocondensation of such 1,3-dinucleophiles with
unsubstituted malonates are known to react not in a 1:1
ratio, but a second equivalent malonate reacts with the
primary cyclocondensation product to give pyrono fused
hydroxy-2-pyridones, quinolones or related heterocycles
[4-6]. These pyrones are valuable intermediates and offer a
high flexibility for further substitution patterns, which are
of interest in our projects for new syntheses of fused
contain two biologically active structure elements, an 4-
hydroxypyridone together with the indole system.
Recently we could show [2] that 2,3,3-trimethyl-3H-
indoles react with 2-substituted dialkyl or bis(2,4,6-
trichlorophenyl) malonates by cyclocondensation to 8-
hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]indol-6-ones.
This means that the fixed imino moiety of the 3H-indole A
isomerizes to the 1,3-dinucleophilic enamine structure B
having an exocyclic double bond which gives by cyclo-
condensation with malonates fused hydroxy-2-pyridones
of type C, similar to other syntheses of such pyridones [3].
The other possible enamine reaction by attack of the aro-

298
T. Kappe, P. Roschger, B. Schuiki and W. Stadlbauer
Vol. 40
heterocycles containing the biologically active 4-hydroxy-
2-pyridone moiety.
7a,b with 90% sulfuric acid and yielded in excellent yields
the 7-unsubstituted 9-chloro-8-hydroxy-10,10-dimethyl-
10H-pyrido[1,2-a]indol-6-ones 8a,b. However, the reac-
tion temperature had to be raised from 140 to 165 °C to
obtain a similar reaction speed as obtained for the synthesis
of 6, probably caused by the deactivating effect of the
chloro substituent in position 9.
The reaction of 2,3,3-trimethyl-3H-indoles 1a,b with
two equivalents of diethyl malonate (2) in refluxing
diphenylether afforded in 68-78% yield the 11H-
benzo[b]pyrano[3,2-f]indolizinediones 3a,b. During the
cyclocondensation the liberated ethanol had to be removed
by distillation, because otherwise lower yields were
obtained. The stop of ethanol liberation is also a good hint
for the reaction time. The cleavage of the pyrano ring in
the literature follows two methods: either alkaline hydroly-
sis of the cyclic ester to a β-keto acid, which decarboxy-
lates upon acidification to the acetyl group [5,6], or chlori-
nation of the cyclic malonyl system with sulfuryl chloride,
which gives in the first step an instable 3,3-dichloro
pyrane-2,4-dione, and reacts then via a β-keto acid to a
dichloroacetyl group [7]. The alkaline ring opening reac-
tion was performed by an improved method we have
developed for quinolones [5] using sodium hydroxide in
glycole/water as solvent. This offers two advantages: the
boiling point of the mixture is raised to about 140 °C, and
the sodium salts of 3 are well soluble, in contrast to solely
water as solvent. The reaction was finished after one hour
and the products were obtained in high yield and high
purity. When only water was used as solvent, 4a was
obtained in good yield after several hours, whereas the
reaction to 4b was not finished after 24 hours with a yield
of less than 50%.
Removal of the acetyl group of 4a,b to give 7-unsubsti-
tuted 8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]indol-
6-ones 6a,b was performed via an ipso substitution with
90% sulfuric acid using an adapted procedure developed
for corresponding quinolones [5].
Recently we could show that chlorination of pyrono-
quinolones and pyronopyridones with sulfuryl chloride
gives in an electrophilic substitution as unstable intermedi-
ates 3,3-dichloropyrane-2,4-diones which are hydrolyzed
during the aqueous work-up due to the rather strong acidic
conditions to unstable β-keto acids and decarboxylate then
readily to the 3-dichloroacetyl-4-hydroxyquinolones or
pyridones [7,8]. Using this reaction sequence, 11H-
benzo[b]pyrano[3,2-f]indolizindiones 3a,b gave in
excellent yields 9-chloro-7-dichloroacetyl-8-hydroxy-
10,10-dimethyl-10H-pyrido[1,2-a]indol-6-ones 5a,b. In
both cases it was found that also the unsubstituted pyridone
moiety at position 12 of the pyrone 3a,b was chlorinated
too and thus gave 9-chlorosubstituted pyrido[1,2-a]indol-6-
ones 5. Reaction of dichloroacetylpyrido[1,2-a]indol-6-
ones 5a,b with zinc in a mixture of ethanol and glacial
acetic acid afforded a selective reduction to the 7-acetyl-9-
chloro-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]indol-
6-ones 7a,b. The chloro substituent in position 9 remained
unchanged, and also the 2-chloro substituent in the benzo
part of 7b. Deacetylation was again achieved by heating of
In the second part of this work the reaction of 2,3-dihydro-
1H-indoles 9a,b with diethyl malonate (2) was investigated.
2-Methyl-2,3-dihydro-1H-indole 9a is commercially avail-
able, 2,3,3-trimethyl-2,3-dihydro-1H-indole 9b was obtained

Mar-Apr 2003
Synthesis and Reactions of 11H-Benzo[b]pyrano[3,2-f]indolizines
299
by reduction of the C=N double bond of 2,3,3-trimethyl-3H-
indole (1a) with sodium borohydride without affection of the
aromatic ring. The reaction of 2,3-dihydro-1H-indoles 9a,b
with diethyl malonate (2) gave again pyrono compounds,
however in this case the attack of the first equivalent of
diethyl malonate (2) was directed to the aromatic ring due to
the enamine character of 9. As primary cyclization product
resulted - as outlined in Scheme 1 - the pyrrolo[3,2,1-ij]-
quinoline structure of type F. Cyclocondensation of the sec-
ond equivalent of diethyl malonate (2) formed in good yields
8-hydroxy-5-methyl-4,5-dihydropyrrolo[3,2,1-ij]pyrano-
[3,2-c]quinoline-7,10-diones 10a,b.
Alkaline ring opening of 10 was performed in a similar
manner as described for the sequence 3 → 4 with sodium
hydroxide in glycole/water as solvent and resulted in the
isolation of 5-acetyl-6-hydroxy-2-methyl-1,2-dihydro-4H-
pyrrolo[3,2,1-ij]quinolin-4-ones 11a,b. The cleavage of
the 5-acetyl group could be achieved similar to the
sequence 4 → 6 by ipso-substitution with 90% sulfuric
acid and gave in good yields the 5-unsubstituted 6-
hydroxy-2-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quino-
lin-4-ones 13a,b.
The ring cleavage of the pyrone ring of pyrrolo[3,2,1-ij]-
pyrano[3,2-c]quinolin-7,10-diones 10a,b with sulfuryl chlo-
ride was performed as described in the sequence 3 → 5,
either in glacial acetic acid or in dioxane as solvent and gave
in medium yields 5-dichloracetyl-6-hydroxy-2-methyl-1,2-
dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-ones 12a,b.
Dichloroacetyl compounds of type 12 are versatile interme-
diates for further functionalization of position 5 of the hete-
rocyclic ring. As an example, the reaction of 12a,b with
sodium azide is described. In the first step the chloro atoms
were nucleophilic exchanged against the azido group to pro-
duce a geminal diazide as unstable intermediate [9,10]. In a
subsequent reaction step, nitrogen was evolved and a tetra-
zole ring formed by reaction of the nitrene moiety with the
azide moiety, which gave 6-hydroxy-2-methyl-5-(1H-tetra-
zol-5-ylcarbonyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quino-
lin-4-ones 14a,b. This class of tetrazol-5-ylcarbonyl hetero-
cyclic compound is if interest because of safener properties
in herbicide screening programs [10,11].
monitored by thin layer chromatography, carried out on 0.2 mm
silica gel 60 F-254 (Merck) plates using uv light (254 and 366
nm) for detection. Common reagent-grade chemicals are either
commercially available and were used without further purifica-
tion or prepared by standard literature procedures.
2,3,3-Trimethyl-3H-indole (1a) and 5-chloro-2,3,3-trimethyl-
3H-indole (1b) were prepared according to the procedure
described in ref. [2]. 2-Methyl-2,3-dihydro-1H-indole (9a) is
commercially available (e.g. Aldrich M3,840-0).
EXPERIMENTAL
Melting points were determined on a Gallenkamp Melting
Point Apparatus, Model MFB-595 in open capillary tubes.
Infrared spectra were taken as potassium bromide pellets on a
Perkin-Elmer 298 or a Galaxy Series FTIR 7000 spectropho-
tometer. The H nmr spectra were recorded on a Bruker AMX
instrument (360 MHz) or a Bruker Avance DRX (500 MHz);
nmr spectra were recorded on a Bruker AM 360 instrument (90
MHz). Chemical shifts are reported in ppm from internal tetram-
ethylsilane standard and are given in δ-units. Microanalyses were
performed on a Fisons elemental analyzer, Mod. EA1108 and are
within ±0.4 of the theoretical percentages. All reactions were
1
13
C
4-Hydroxy-11,11-dimethyl-11H-benzo[b]pyrano[3,2-f]-
indolizine-2,5-dione (3a).
A solution of 2,3,3-trimethyl-3H-indole (1a) (15.9 g, 0.1 mol),
diethyl malonate (2) (32.1 g, 0.2 mol) in diphenylether (50 g) was
heated for about 1.5 hours to 200-250 °C. During this time

300
T. Kappe, P. Roschger, B. Schuiki and W. Stadlbauer
Vol. 40
ethanol (about 22 mL) was liberated. When the liberation of
ethanol had stopped, the reaction mixture was cooled to about 50
°C and to the crystal mush methanol (50 mL) was added. After
several hours the solid was collected by suction filtration and
washed with methanol until the filtrate was only pale yellowish.
Then the precipitate was washed with diethyl ether and dried.
The yield was 20.1 g (68%), yellow prisms, mp 243-248 °C
(glacial acetic acid); ir: 3070 w, 1730 s, 1660 s, 1620 m, 1560 s
acetyl-CH ), 6.40 (s, 1 H, 9-H), 7.3 (dd, J = 2 and 8 Hz, 1 H,
3-H), 7.65 (d, J = 2 Hz, 1 H, 1-H), 8.3 (d, J = 8 Hz, 1 H, 4-H).
3
Anal. Calcd. for C
H ClNO : C, 63.27; H, 4.65; N, 4.61.
16 14 3
Found: C, 62.93; H, 4.92; N, 4.37.
9-Chloro-7-dichloroacetyl-8-hydroxy-10,10-dimethyl-10H-
pyrido[1,2-a]indol-6-one (5a).
To a suspension of benzo[b]pyrano[3,2-f]indolizinedione 3a
(14.77 g, 50 mmol) in glacial acetic acid (300 mL) sulfurylchlo-
ride (35 mL, 0.43 mol) was added and stirred for 20 min at 20 °C.
Then the mixture was poured onto ice/water (300 mL), and after
12 hours the precipitate was collected by suction filtration. The
yield was 16.6 g (89%), yellow prisms, mp 155-156 °C (ethanol);
-1 1
cm ; H nmr (CF COOH): δ = 1.50 (s, 6 H, 2 CH ), 5.75 (s, 1 H,
3
3
3-H), 6.75 (s, 1 H, 12-H), 7.20-7.50 (m, 2 H, ArH), 8.30 (dd, J =
2 and 8 Hz, 1 H, 7-H).
Anal. Calcd. for C
H NO : C; 69.15; H, 4.44; N, 4.74.
17 13 4
Found: C, 69.51; H 4.52; N, 4.72.
-1 1
ir: 3040 w, 2970 w, 1650 s, 1610 s, 1575 m, 1530 m cm ; H nmr
9-Chloro-4-hydroxy-11,11-dimethyl-11H-benzo[b]pyrano[3,2-f]-
indolizin-2,5-dione (3b).
(CDCl ): δ = 1.80 (s, 6 H, 2 CH ), 7.20-7.60 (m, 3 H, ArH), 7.95
3
3
(s, 1 H, dichloroacetyl-H), 8.60 (dd, J = 2 and 8 Hz, 1 H, 4-H).
5-Chloro-2,3,3-trimethyl-3H-indole (1b) (19.3 g, 0.1 mol) and
diethyl malonate (2) (32.1 g, 0.2 mol) were reacted for 2 hours as
described for 1a. The still hot reaction mixture was then poured
quickly under vigorous stirring into methanol (500 mL) (atten-
tion: danger of local superheating). Further work up was per-
formed as described for 1a. The yield was 25.8 g (78%), yellow
prisms, mp 304 °C (dec.) (glacial acetic acid); ir: 3090 w, 2970 w,
Anal. Calcd. for C Cl NO : C, 51.57; H, 3.25; N, 3.76.
Found: C, 51.24; H, 3.23; N, 3.76.
H
16 12
3
3
2,9-Dichloro-7-dichloroacetyl-8-hydroxy-10,10-dimethyl-10H-
pyrido[1,2-a]indol-6-one (5b).
Benzo[b]pyrano[3,2-f]indolizinedione 3b (16.49 g, 50 mmol)
was reacted and worked up as described for 5a. The yield was
18.3 g (90%), yellow prisms, mp 174-176 °C (ethanol); ir: 3020
-1
1
1670 s, 1630 m, 1560 m cm ; H nmr (CF COOH): δ = 1.50 (s,
3
-1
1
6 H, 2 CH ), 5.70 (s, 1 H, 3-H), 6.70 (s, 1 H, 12-H), 7.10-7.40 (m,
w, 2970 w, 1650 s, 1615 s, 1580 m, 1525 m cm ; H nmr
(CDCl ): δ = 1.85 (s, 6 H, 2 CH ), 7.20-7.55 (m, 2 H, ArH), 7.95
3
2 H, ArH), 8.25 (d, J = 8 Hz, 1 H, 7-H).
3
3
Anal. Calcd. for C
H
ClNO : C, 61.92; H, 3.67; N, 4.25.
(s, 1 H, dichloroacetyl-H), 8.60 (J = 8 Hz, 1 H, 4-H).
17 12
4
Found: C, 61.97; H, 3.67; N, 4.13.
Anal. Calcd. for C H Cl NO : C, 47.21; H, 2.72; N, 3.44.
16 11
4
3
Found: C, 47.53; H, 2.78; N, 3.36.
7-Acetyl-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]indol-6-
one (4a).
8-Hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]indol-6-one (6a).
To a suspension of benzo[b]pyrano[3,2-f]indolizinedione 3a
(14.77 g, 50 mmol) in 1,2-ethanediole (100 mL), a solution of
sodium hydroxide (10.0 g, 250 mmol) in water (10 mL) was
added and the mixture heated under reflux for 1 hour. During the
first 10 minutes a strong foaming of the mixture was observed
(evolution of carbon dioxide). In this period the reaction flask
was shaken several times to dissolve the starting material. At the
end of the reaction time, sodium carbonate precipitated and the
solution began to bump which made a careful control of heating
necessary. After cooling, the mixture was poured onto ice/water
(300 mL) and acidified with conc. hydrochloric acid to pH = 1.
Attention: the evolution of carbon dioxide from the formed
sodium carbonate caused strong foaming of the solution. The pre-
cipitate was allowed to stand several hours and then collected by
suction filtration and washed with water until neutral. The yield
was 12.5 g (93%), light yellowish prisms, mp 161-163 °C
(methanol); ir: 2960 w, 2920 w, 2860 w, 1665 s, 1635 m, 1600 m,
A solution of acetyl-pyrido[1,2-a]indolone 4a (10.77 g, 40
mmol) in 90% sulfuric acid (20 mL) was heated for 20 min to 140
°C. After cooling to 20 °C the mixture was poured onto ice/water
(300 mL), the formed precipitate allowed to stand overnight and
then collected by suction filtration and washed with water until
neutral. The yield was 8.7 g (96%), colorless prisms, mp 261-264
°C (glacial acetic acid); ir: 3200-2300 b, 1640 m, 1605 s, 1555 s
-1
1
cm ; H nmr (CF COOH): δ = 1.65 (s, 6 H, 2 CH ), 6.85 (d, J =
3
3
2 Hz, 1 H, H-9), 7.05 (d, J = 2 Hz, 1 H, 7-H), 7.40-7.70 (m, 3 H,
ArH), 8.30 (dd, J = 2 and 8 Hz, 1 H, 4-H).
Anal. Calcd. for C
H NO : C, 73.99; H, 5.77; N, 6.16.
14 13 2
Found: C, 73.97; H, 5.58; N, 6.09.
2-Chloro-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]indol-6-
one (6b).
Acetylpyrido[1,2-a]indolone 4b (12.15 g, 40 mmol) was
reacted and worked up as described for 6a. The yield was 9.9 g
(95%), colorless prisms, mp 301 °C (dec) (glacial acetic acid); ir:
-1
1
1550 m cm ; H nmr (DMSO-d ): δ = 1.50 (s, 6 H, 2 CH ), 2.65
6
3
-1
1
(s, 3 H, acetyl-CH ), 6.40 (s, 1 H, 9-H), 7.10-7.60 (m, 3 H, ArH),
3150-2300 b, 1640 m, 1605 m, 1550 s cm
;
H nmr
3
(CF COOH): δ = 1.65 (s, 6 H, 2 CH ), 6.75 (d, J = 2 Hz, 1 H, 9-
8.35 (dd, J = 2 and 8 Hz, 1 H, 4-H).
3
3
H), 6.95 (d, J = 2 Hz, 1 H, 7-H), 7.30-7.55 (m, 2 H, ArH), 8.2 (d,
J = 8 Hz, 1 H, 4-H).
Anal. Calcd. for C
Found: C, 71.75; H, 5.55; N, 5.04.
H NO : C, 71.36; H, 5.61; N, 5.20.
16 15 3
Anal. Calcd. for C
Found: C, 63.94; H, 4.56; N, 5.22.
H ClNO : C, 64.25; H, 4.62; N, 5.35.
14 12 2
7-Acetyl-2-chloro-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]-
indol-6-one (4b).
7-Acetyl-9-chloro-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]i-
ndol-6-one (7a).
Benzo[b]pyrano[3,2-f]indolizinedione 3b (16.49 g, 50 mmol)
was reacted and worked up as described for 4a. The yield was
14.1 g (93%); light yellowish prisms, mp 188-190.5 °C
Dichloroacetylpyrido[1,2-a]indolone 5a (8.19 g, 22 mmol) was
dissolved in a boiling mixture of ethanol (300 mL) and glacial
acetic acid (50 mL). Then zinc powder (18 g) was added quickly,
-1
/ethanol/water); ir: 2970 w, 1655 s, 1630 s, 1590 s, 1540 m cm ;
1
H nmr (DMSO-d ): δ = 1.50 (s, 6 H, 2 CH ), 2.60 (s, 3 H,
6
3

Mar-Apr 2003
Synthesis and Reactions of 11H-Benzo[b]pyrano[3,2-f]indolizines
301
and then the reaction mixture was filtered immediately to remove
unreacted zinc powder. The filtrate was concentrated under
reduced pressure to about 40 mL and then diluted with ice/water
(400 mL). The precipitate was kept at 4 °C for 24 hours and then
collected by suction filtration. The yield was 5.80 g (87%), color-
less prisms, mp 147-148.5 °C (glacial acetic acid); ir: 3000 w,
3-CH ), 1.24 (d, J = 7 Hz, 3 H, 2-CH ), 1.35 (s, 3 H, 3-CH ), 3.55 (q,
3 3 3
1 H, 2-H), 3.65 (s, b, 1 H, NH), 6.62-7.13 (m, 4 H, ArH).
8-Hydroxy-5-methyl-4,5-dihydro-pyrrolo[3,2,1-ij]pyrano[3,2-c]-
quinoline-7,10-dione (10a).
Methylindoline 1a (47.4 g, 0.36 mol) and diethyl malonate (2)
(114.34 g, 0.71 mol) were reacted for about 9 hours and work up
was as described for 3a. The yield was 61.5 g (64%) yellow
prisms, mp 210 °C (1-butanol); ir: 1760 m, 1735 s, 1675 s, 1620
-1
1
2930 w, 1665 s, 1650 w, 1610 w, 1590 m, 1545 m cm ; H nmr
(CDCl ): δ = 1.75 (s, 6 H, 2 CH ), 2.70 (s, 3 H, acetyl-CH ), 7.10-
3
3
3
7.40 (m, 3 H, ArH), 8.60 (dd, J = 2 and 8 Hz, 4-H).
-1
1
m, 1610 m, 1560 m cm ; H nmr (CDCl ): δ = 1.65 (d, J = 7 Hz,
Anal. Calcd. for C ClNO : C, 63.27; H, 4.65; N, 4.61.
H
3
16 14
3
3 H, CH ), 3.10 (dd, J = 1.5 and 7 Hz, 1 H, 4-H), 3.75 (dd, J = 1.5
Found: C, 63.65; H, 4.62; N, 4.60.
3
and 7 Hz, 1 H, 4-H), 5.15-5.24 (m, 1 H, H-5), 5.65 (s, 1 H, 9-H),
7.30-7.60 (m, 2 H, ArH), 7.95 (dd, J = 1.5 and 7 Hz, 1 H, 1-H),
13.2 (s, 1 H, OH).
7-Acetyl-2,9-dichloro-8-hydroxy-10,10-dimethyl-10H-
pyrido[1,2-a]indol-6-one (7b).
Anal. Calcd. for C
Found: C, 67.08; H, 3.95; N, 5.14.
H NO : C, 66.91; H, 4.12; N, 5.20.
Dichloroacetylpyrido[1,2-a]indolone 5b (8.95 g, 22 mmol)
was reacted and worked up as described for 7a. The yield was
6.95 g (93%), colorless prisms, mp 236-238 °C (glacial acetic
15 11 4
8-Hydroxy-4,4,5-trimethyl-4,5-dihydropyrrolo[3,2,1-ij]pyrano-
[3,2-c]quinoline-7,10-dione (10b).
-1
acid); ir: 3000 w, 1665 s, 1615 m, 1595 m, 1585 m, 1545 m cm ;
1
H nmr (CDCl ): δ = 1.75 (s, 6 H, 2 CH ), 2.75 (s, 3 H, acetyl-
3
3
Trimethylindoline 9b (13.2 g, 0.082 mol) and diethyl malonate
(2) (40.0 g, 0.25 mol) were reacted for 2.5 hours and work up was
as described for 3a. The yield was 18.9 g (78%), yellow needles,
CH ), 7.10-7.40 (m, 2 H, ArH), 8.50 (J = 8 Hz, 1 H, 4-H).
3
Anal. Calcd. for C
H Cl NO : C; 56.83; H; 3.87; N; 4.14.
16 13 2 3
Found: C; 56.70; H; 3.87; N; 4.05.
-1
mp 203 °C (1-butanol); ir: 2940 w, 1740 s, 1660 s, 1550 s cm ;
9-Chloro-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]indol-6-
one (8a).
1
H nmr (CDCl ): δ = 1.30 (s, 3 H, 4-CH ), 1.50 (d, J= 7 Hz, 3 H,
3
3
5-CH ), 1.55 (s, 3 H, 4-CH ), 4.70 (q, J = 7 Hz, 1 H, 5-H), 5.65
3
3
(s, 1 H, 9-H), 7.30-7.60 (m, 2 H, ArH), 7.95 (dd, J = 1.5 and 7 Hz,
1 H, 1-H), 13.25 (s, 1 H, OH).
Acetylpyrido[1,2-a]indolone 7a (3.04 g, 10 mmol) and 90 %
sulfuric acid (15 mL) was reacted for 15 min at 155-165 °C and
worked up as described for 6a. The yield was 2.28 g (87%), col-
orless prisms, mp 287-289 °C (glacial acetic acid); ir: 3200-2300
Anal. Calcd. for C
H NO : C, 68.68; H, 5.09; N, 4.71.
17 15 4
Found: C, 68.59; H, 5.01; N, 4.60.
-1
1
b, 1650 m, 1610 m, 1540 s, cm ; H nmr (DMSO-d ): δ = 1.70
6
5-Acetyl-6-hydroxy-2-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]-
quinolin-4-one (11a).
(s, 6 H, 2 CH ), 5.80 (s, 1 H, 7-H), 7.05-7.55 (m, 3 H, ArH), 8.35
3
(dd, 2 and 8 Hz, 1 H, 4-H).
Pyrrolo[3,2,1-ij]pyrano[3,2-c]quinolinedione 10a (13.45 g,
0.05 mol) was reacted and work up was as described for 4a. The
yield was 10.05 g (83%), colorless prisms, mp 163 °C (glacial
Anal. Calcd. for C
Found: C, 64.08; H, 4.72; N, 5.13.
H ClNO : C, 64.25; H, 4.62; N, 5.35.
14 12 2
2,9-Dichloro-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]-
indol-6-one (8b).
-1
1
acetic acid); ir: 2910 w, 1740 w, 1650 s, 1610 s, 1550 m cm ; H
nmr (CDCl ): δ = 1.46 (d, J = 7 Hz, 3 H, Ch ), 2.70 (s, 3 H,
3
3
acetyl-CH ), 2.92 (dd, J = 1.5 and 7 Hz, 1 H, H-1), 3.57 (dd, J =
Acetylpyrido[1,2-a]indolone 7b (3.38 g, 10 mmol) was
reacted for 15 min at 155-165 °C and worked up as described for
6a. The yield was 2.65 g (89%), colorless prisms, mp 281.5-
283.5 °C (glacial acetic acid); ir: 3300-2400 b, 1635 m, 1610 m,
3
1.5 and 7 Hz, 1 H, H-1), 4.75-4.95 (m, 1 H, H-2), 7.20 (m, 1 H,
H-8), 7.58 (dd, J = 1.5 and 7 Hz, 1 H, H-8), 7.68 (dd, J = 1.5 and
7 Hz, 1 H, H-7).
-1
1
Anal. Calcd. for C
H NO : C, 69.12; H, 5.39; N, 5.76.
1560 s cm ; H nmr (DMSO-d ): δ = 1.70 (s, 6 H, 2 CH ), 5.85
14 13 3
6
3
(s, 1 H, 7-H), 7.40 (dd, J = 2 and 8 Hz, 1 H, 3-H), 7.70 (d, J = 8
Hz, 1 H, 1-H), 8.50 (d, J = 8 Hz, 1 H, 4-H).
Found: C, 69.21; H, 5.27; N, 5.63.
5-Acetyl-6-hydroxy-1,1,2-trimethyl-1,2-dihydro-4H-pyrrolo-
[3,2,1-ij]quinolin-4-one (11b).
Anal. Calcd. for C H Cl NO : C, 56.78; H, 3.74; N, 4.73.
14 11
2
2
Found: C, 56.99; H, 3.67; N, 4.53.
Pyrrolo[3,2,1-ij]pyrano[3,2-c]quinolinedione 10b (8.92 g,
0.03 mol) in 1,2-dihydroxyethane (70 mL) was reacted and
worked up as described for 4a. The yield was 5.86 g (72%), beige
prisms, mp 144 °C (glacial acetic acid); ir: 2960 w, 1700 sh, 1650
2,3,3-Trimethyl-2,3-dihydro-1H-indole (9b).
This compound was prepared using an adapted literature proce-
dure [12]. To a solution of 2,3,3-trimethyl-3H-indole (1a) in 80%
aqueous methanol (150 mL) at 0 °C sodium borohydride (5.3 g, 0.14
mol) was added in portions keeping the temperature between 0-10
°C. The reaction mixture was then stirred at 5 °C for 10 hours fol-
lowed by 3 hours at reflux. After cooling, the solvent was removed
under reduced pressure and the yellow residual solution diluted with
water (50 mL) and made alkaline with 2 N sodium hydroxide solu-
tion. The product was extracted with diethylether (2x 100 mL) and
the extract dried with sodium sulfate, filtered and the ether removed
under reduced pressure. Vacuum distillation of the yellow residue
-1
1
s, 1615 s, 1550 b, w cm ; H nmr (CDCl ): δ = 1.30 (s, 3 H, 1-
3
CH ), 1.40 (s, 3 H, 1-CH ), 1.44 (d, J = 7 Hz, 3 H, 2-CH ), 2.82
3
3
3
(s, 3 H, acetyl-CH ), 4.54 (q, 1 H, H-2), 7.10-7.43 (m, 2 H, ArH),
3
7.8 (dd, J = 1.5 and 7 Hz, 1 H, H-7).
Anal. Calcd. for C
H NO : C, 70.83; H, 6.32; N, 5.16.
16 17 3
Found: C, 70.79; H, 6.43; N, 5.10.
5-Dichloracetyl-6-hydroxy-2-methyl-1,2-dihydro-4H-pyrrolo-
[3,2,1-ij]quinolin-4-one (12a).
gave a bright yellow oil (31.45 g, 75%), bp 118 °C/19 Torr (lit. bp
To a suspension of pyrrolo[3,2,1-ij]pyrano[3,2-c]quinolindione
10a (5.39 g, 0.02 mol) in glacial acetic acid (50 mL)
1
234-235 °C/753 Torr [13]); H nmr (CDCl ): δ = 1.10 (s, 3 H,
3

302
T. Kappe, P. Roschger, B. Schuiki and W. Stadlbauer
Vol. 40
sulfurylchloride (10 mL, 0.12 mol) was added in portions to keep
the temperature below 50 °C. After 10 minutes at this temperature,
the mixture was heated to reflux for 5 minutes, cooled to room
temperature and poured onto ice/water (500 mL). The resulting
yellow oil was stirred with water for 6 hours, the formed precipi-
tate was collected by suction filtration and washed with water until
neutral. The yield was 3.09 g (50%), yellow prisms, mp 178 °C
(glacial acetic acid); ir: 3020 w, 1645 s, 1630 sh, 1615 s, 1550 m
dimethylformamide (50 mL) was stirred at 20 °C for 48 h and
then poured onto ice/water (500 mL). This mixture was acidified
with 2 M hydrochloric acid in small portions (attention: HN is
3
set free), the resulting precipitate was collected by suction
filtered and washed with water. The yield was 2.02 g (68%) col-
orless prisms, mp 211 °C (glacial acetic acid); ir: 2970 w, 1660
-1
1
sh, 1650 s, 1625 sh, 1615 s, 1590 cm ; H nmr (DMSO-d ): δ =
6
1.41 (d, J = 7 Hz, 3 H, CH ), 2.95 (dd, J = 1.5 and 7 Hz, 1 H,
3
-1
1
cm ; H nmr (CDCl ): δ = 1.60 (d, J = 7 Hz, 3 H, CH ); 3.0 (dd,
1-H), 3.42 (s, b, 1 H, tetrazolyl-H), 3.62 (m, 1 H, 1-H), 4.80-4.86
(m, 1 H, 2-H), 7.25 (m, 1 H, 8-H), 7.57 (dd, J = 1.5 and 7 Hz, 1 H,
9-H), 7.79 (dd, J = 1.5 and 7 Hz, 1 H, 7-H).
3
3
J = 1.5 and 7 Hz, 1 H, 1-H), 3.60 (dd, J = 1.5 and 7 Hz, 1 H, 1-H),
4.90-5.10 (m, 1 H, 2-H), 7.10-7.55 (m, 2 H, ArH), 7.85 (dd, J = 1.5
and 7 Hz, 1 H, 7-H), 8.05 (s, 1 H, CHCl ), 15.4 (s, 1 H, OH).
Anal. Calcd. for C H N O : C, 56.57; H, 3.73; N, 23.56.
2
14 11
5 3
Anal. Calcd. for C H Cl NO : C, 53.87; H, 3.55; Cl, 22.72;
Found C, 56.33; H, 3.66; N, 23.54.
14 11
2
3
N, 4.49. Found: C, 54.01; H, 3.39; Cl, 22.98; N, 4.41.
6-Hydroxy-1,1,2-trimethyl-5-(1H-tetrazol-5-ylcarbonyl)-1,2-
dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (14b).
5-Dichloracetyl-6-hydroxy-1,1,2-trimethyl-1,2-dihydro-4H-
pyrrolo[3,2,1-ij]quinolin-4-one (12b).
Dichloroacetylpyrrolo[3,2,1-ij]quinolinone 12b (3.4 g,
0.01 mol) was reacted and work up was as described for 14a. The
yield was 1.82 g (56%), colorless prisms, mp 201 °C (glacial
Pyrrolo[3,2,1-ij]pyrano[3,2-c]quinolindione 10b (4.46 g, 15
mmol) in dioxane (35 mL) was reacted with sulfurylchloride (3.2
mL, 40 mmol) and work up was as described for 12a. The yield
was 3.05 g (60%), yellow prisms, mp 112 °C (glacial acetic acid);
-1
1
acetic acid); ir: 2960 w, 1645 sh, 1600 s, b, 1549 m, b cm ; H
nmr (DMSO-d ): δ = 1.39 (s, 3 H, 1-CH ), 1.50 (s, 3 H, 1-CH),
6
3
-1
1
ir: 3030 w, 2960 w sh, 1640 s, b, 1610 s, 1550 s, b cm ; H nmr
1.52 (d, J = 7 Hz, 3 H, 2-CH ), 4.70 (q, J = 7 Hz, 1 H, 2-H), 7.35
3
(CDCl ): δ = 1.35 (s, 3 H, 1-CH ), 1.40 (s, 3 H, 1-CH ), 1.45 (d,
(m, 1 H, 8-H), 7.55 (dd, J = 1.5 and 7 Hz, 1 H, 9-H), 8.0 (dd, J =
1.5 and 7 Hz, 1 H, 7-H).
3
3
3
J = 7 Hz, 3 H, 2-CH ), 4.58 (q, 1 H, 1-H), 7.15-7.50 (m, 2 H,
3
ArH), 7.85 (dd, J = 1.5 and 7 Hz, 1 H, H-7), 8.05 (s, 1 H, CHCl ).
2
Anal. Calcd. for C
H N O : C, 59.07; H, 4.65; N, 21.53.
16 15 5 3
Anal. Calcd. for C
H Cl NO : C, 56.49; H, 4.44; N, 4.12.
16 15 2 3
Found: C, 59.04; H, 4.52; N, 21.50.
Found: C, 56.40; H, 4.20; N, 3.98.
6-Hydroxy-2-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-
4-one (13a).
REFERENCES AND NOTES
Acetylpyrrolo[3,2,1-ij]quinolinone 11a (7.29 g, 0.03 mol) and
90% sulfuric acid (25 mL) were reacted for 10 minutes and work
up was as described for 6a. The yield was 3.82 g (63%), colorless
prisms, mp 307 °C (dimethylformamide); ir: 2930 w, 2600-2400
[1] Organic Azides in Heterocyclic Synthesis, Part 32; Part 31:
A. E. Täubl, K. Langhans, T. Kappe and W. Stadlbauer,
J. Heterocyclic Chem., 39, 1259 (2002).
[2] T. Kappe, F. Frühwirth, P. Roschger, B. Jocham,
J. Kremsner and W. Stadlbauer, J. Heterocyclic Chem., 39, 391 (2002).
[3] W. Stadlbauer, E.-S. Badawey, G. Hojas, P. Roschger and
T. Kappe, Molecules, 6, 345 (2001).
[4] R. E. Bowman, A. Campbell and E. M. Tanner, J. Chem.
Soc., 444 (1959).
[5] P. Roschger and W. Stadlbauer, Liebigs Ann. Chem., 821
(1990); W. Fiala, P. Roschger and W. Stadlbauer, J. Heterocyclic
Chem., 29, 225 (1992).
-1
1
b, 1640 s, 1620 m, 1585 s cm ; H nmr (DMSO-d ): δ = 1.45 (d,
6
J = 7 Hz, 3 H, CH ), 2.94 (dd, J = 1.5 and 7 Hz, 1 H, 1-H), 3.6
3
(dd, J = 1.5 and 7 Hz, 1 H, 1-H), 4.75-4.92 (m, 1 H, 2-H), 5.77 (s,
1 H, 5-H), 7.10-7.57 (m, 3 H, ArH).
Anal. Calcd. for C
H NO : C, 71.63; H, 5.51; N, 6.96.
12 11 2
Found: C, 71.45; H, 5.32; N, 6.73.
6-Hydroxy-1,1,2-trimethyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]-
quinolin-4-one (13b).
[6] T. Kappe, Il Farmaco, 54, 309 (1999).
[7] C. O. Kappe and T. Kappe, J. Heterocyclic Chem., 26, 1555
(1989).
[8] T. Kappe, R. Aigner, P. Hohengassner and W. Stadlbauer, J.
Prakt. Chem., 336, 596 (1994).
Acetyl-pyrrolo[3,2,1-ij]quinolinone 11b (5.21 g, 0.0192 mol)
and 90% sulfuric acid (25 mL) were reacted for 10 minutes at 135
°C and work up was as described for 6a. The yield was 2.2 g
(63%), colorless prisms, mp 264 °C (dimethylformamide); ir:
[9] K. Faber and T. Kappe, J. Heterocyclic Chem., 21, 1881
(1984); T. Kappe and C. O. Kappe in “Progress in Heterocyclic
Chemistry” (H. Suschitzky and G. W. Gribble, eds), vol. 8, Pergamon,
Oxford, UK, 1996, pp 1-13.
[10] T. Krivitchenko, Dissertation, University of Graz, 1999.
[11] J. J. Kulagowski, R. Baker, N. Curtis, P. D. Leeson, I. M.
Mawer, A. M. Mosley, M. P. Ridgilli, M. Rowley, I. Stansfield, A. C.
Foster, S. Grimwood, R. G. Hill, J. A. Kemp, G. R. Marshall, K. L.
Saywell and M. D. Tricklebank, J. Med. Chem., 37, 1402 (1994).
[12] N. P. Buu-Hoi, P. Jaquinon and T. B. Loc, J. Chem. Soc.,
738 (1958); S. Sakai, M. Wakabayashi and M. Nishina, Yakugaku
Zasshi, 89, 1061 (1969); Chem. Abstr., 72, 3308d (1970).
[13] A. Ferratini, Gazz. Chim. Ital., 23 II, 112 (1893).
-1
1
2960 w, 1645 m, 1620 m, 1590 s, b, 1500 s, b cm ; H nmr
(DMSO-d ): δ = 1.28 (s, 3 H, 1-CH ), 1.34 (d, J = 7 Hz, 3 H, 2-
6
3
CH ), 1.36 (s, 3 H, 1-CH ), 4.38 (q, J = 7 Hz, 1 H, 1-H), 5.78 (s,
3
3
1 H, 5-H), 7.15 (m, 1 H, 8-H), 7.20 (dd, J = 1.5 and 7 Hz, 1 H, 9-
H), 7.28 (dd, J = 1.5 and 7 Hz, 1 H, 7-H).
Anal. Calcd. for C
H NO : C, 73.34; H, 6.59; N, 6.11.
14 15 2
Found: C, 73.60; H, 6.50; N, 5.90.
6-Hydroxy-2-methyl-5-(1H-tetrazol-5-ylcarbonyl)-1,2-dihydro-
4H-pyrrolo[3,2,1-ij]quinolin-4-one (14a).
A mixture of dichloroacetylpyrrolo[3,2,1-ij]quinolinone 12a
(3.15 g, 0.01 mol) and sodium azide (2.6 g, 0.04 mol) in